Investigating the effects of healthy cognitive aging on brain functional connectivity using 4.7 T resting-state functional magnetic resonance imaging.

Functional changes in the aging human brain have been previously reported using functional magnetic resonance imaging (fMRI). Earlier resting-state fMRI studies revealed an age-associated weakening of intra-system functional connectivity (FC) and age-associated strengthening of inter-system FC. However, the majority of such FC studies did not investigate the relationship between age and network amplitude, without which correlation-based measures of FC can be challenging to interpret. Consequently, the main aim of this study was to investigate how three primary measures of resting-state fMRI signal-network amplitude, network topography, and inter-network FC-are affected by healthy cognitive aging. We acquired resting-state fMRI data on a 4.7 T scanner for 105 healthy participants representing the entire adult lifespan (18-85 years of age). To study age differences in network structure, we combined ICA-based network decomposition with sparse graphical models. Older adults displayed lower blood-oxygen-level-dependent (BOLD) signal amplitude in all functional systems, with sensorimotor networks showing the largest age differences. Our age comparisons of network topography and inter-network FC demonstrated a substantial amount of age invariance in the brain's functional architecture. Despite architecture similarities, old adults displayed a loss of communication efficiency in our inter-network FC comparisons, driven primarily by the FC reduction in frontal and parietal association cortices. Together, our results provide a comprehensive overview of age effects on fMRI-based FC.

Effects of childhood adversity on the volumes of the amygdala subnuclei and hippocampal subfields in individuals with major depressive disorder.

Background: Reductions in total hippocampus volume have frequently been reported in MRI studies in major depressive disorder (MDD), but reports of differences in total amygdala volume have been inconsistent. Childhood maltreatment is an important risk factor for MDD in adulthood and may affect the volume of the hippocampus and amygdala. In the present study, we examined associations between the volumes of the amygdala subnuclei and hippocampal subfields and history of childhood maltreatment in participants with MDD. Methods: We recruited 35 patients who met the DSM-IV criteria for MDD and 35 healthy controls. We acquired MRI data sets on a 4.7 T Varian Inova scanner. We manually delineated the amygdala subnuclei (lateral, basal and accessory basal nuclei, and the cortical and centromedial groups) and hippocampal subfields (cornu ammonis, subiculum and dentate gyrus) using reliable volumetric methods. We assessed childhood maltreatment using the Childhood Trauma Questionnaire in participants with MDD. Results: In participants with MDD, a history of childhood maltreatment had significant negative associations with volume in the right amygdala, anterior hippocampus and total cornu ammonis subfield bilaterally. For volumes of the amygdala subnuclei, such effects were limited to the basal, accessory basal and cortical subnuclei in the right hemisphere, but they did not survive correction for multiple comparisons. We did not find significant effects of MDD or antidepressant treatment on volumes of the amygdala subnuclei. Limitations: Our study was a cross-sectional study. Conclusion: Our results provide evidence of negative associations between history of childhood maltreatment and volumes of medial temporal lobe structures in participants with MDD. This may help to identify potential mechanisms by which maltreatment leads to clinical impacts.

Involvement of hippocampal subfields and anterior-posterior subregions in encoding and retrieval of item, spatial, and associative memories: Longitudinal versus transverse axis.

The functional role of the hippocampal formation in episodic memory has been studied using functional magnetic resonance imaging (fMRI) for many years. The hippocampus can be segmented into three major anteroposterior sections, called head, body and tail, and into the Cornu Ammonis (CA), dentate gyrus (DG), and subiculum (Sub) subfields based on its transverse axis. However, the exact role of these subregions and subfields in memory processes is less understood. In the present study we combined ultra-high-resolution structural Magnetic Resonance Imaging (MRI) at 4.7 T with an event-related high-resolution fMRI paradigm based on the 'Designs' subtest of the Wechsler Memory Scale to investigate how the hippocampal subfields and longitudinal subregions are involved in encoding and retrieval of item, spatial, and associative memories. Our results showed that during memory encoding, regardless of the type of memory being learned, all subregions and all subfields were active. During the retrieval phase, on the other hand, we observed an anterior to posterior gradient in hippocampal activity for all subfields and all types of memory. Our findings also confirmed presence of an anterior to posterior gradient in hippocampal activity during spatial learning. Comparing subfield activities to each other revealed that the DG was more active than the CA1-3 and Sub during both encoding and retrieval. Finally, our results showed that for every subfield, encoding vs. retrieval activity differences were larger in the hippocampal head than in the hippocampal body and tail. Furthermore, these encoding vs. retrieval activity differences were similar in all subfields, highlighting the importance of studying both the longitudinal and transverse axis specialization simultaneously. Current findings further elucidate the structure-function relationship between the human hippocampus and episodic memory.

Amygdala subnuclei and healthy cognitive aging.

Amygdala is a group of nuclei involved in the neural circuits of fear, reward learning, and stress. The main goal of this magnetic resonance imaging (MRI) study was to investigate the relationship between age and the amygdala subnuclei volumes in a large cohort of healthy individuals. Our second goal was to determine effects of the apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF) polymorphisms on the amygdala structure. One hundred and twenty-six healthy participants (18-85 years old) were recruited for this study. MRI datasets were acquired on a 4.7 T system. Amygdala was manually segmented into five major subdivisions (lateral, basal, accessory basal nuclei, and cortical, and centromedial groups). The BDNF (methionine and homozygous valine) and APOE genotypes (ε2, homozygous ε3, and ε4) were obtained using single nucleotide polymorphisms. We found significant nonlinear negative associations between age and the total amygdala and its lateral, basal, and accessory basal nuclei volumes, while the cortical amygdala showed a trend. These age-related associations were found only in males but not in females. Centromedial amygdala did not show any relationship with age. We did not observe any statistically significant effects of APOE and BDNF polymorphisms on the amygdala subnuclei volumes. In contrast to APOE ε2 allele carriers, both older APOE ε4 and ε3 allele carriers had smaller lateral, basal, accessory basal nuclei volumes compared to their younger counterparts. This study indicates that amygdala subnuclei might be nonuniformly affected by aging and that age-related association might be gender specific.

Effects of cortisol on hippocampal subfields volumes and memory performance in healthy control subjects and patients with major depressive disorder.

Overactivity of the hypothalamic-pituitary-adrenal (HPA) axis in major depressive disorder (MDD) is among the most consistently replicated biological findings in psychiatry. Magnetic resonance imaging (MRI) studies have consistently demonstrated that hippocampal (HC) volume is decreased in patients with MDD. The improved spatial resolution of high field strength MRI has recently enabled measurements of HC subfield volumes in vivo. The main goal of the present study was to examine the relationship between cortisol concentrations over a day and HC subfield volumes in patients with MDD compared to healthy controls and to investigate whether diurnal cortisol measures are related to memory performance. Fourteen MDD patients with moderate or severe episodes were recruited, together with 14 healthy controls. Imaging was performed using a 4.7T whole-body imaging system. HC subfields and subregions were segmented manually using previously defined protocol. Memory performance was assessed using the Wechsler Memory Scale IV. The salivary cortisol levels were measured over the course of one day. We found that cortisol awakening response to 8h (CAR-8h) was higher in MDD patients compared to controls and that this increase in CAR-8h in MDD patients correlated negatively with left total Cornu Ammonis (CA)1-3 and left HC head volume. In healthy controls mean cortisol levels were negatively associated with right total CA1-3, right HC head, and right total HC volume. In addition, in healthy controls higher CAR-8h was related to worse performance on the immediate content memory. These results provide the first in vivo evidence of the negative associations between cortisol level, CA1-3 HC subfield volume and memory performance in patients with MDD and healthy controls.

Dentate gyrus volume and memory performance in major depressive disorder.

BACKGROUND: Magnetic resonance imaging (MRI) has shown lower hippocampal volume in major depressive disorder (MDD). Patients with MDD have consistently demonstrated worse performance than healthy controls a number of memory tests. Memory functions within the hippocampus in healthy younger subjects appear to be linked to cornu ammonis (CA1-3) and dentate gyrus (DG) subfields. Therefore, the main goal of the present study was to investigate whether memory deficits in MDD patients are related to reduction in hippocampal subfields volumes, particularly DG and CA 1-3. METHODS: 15 MDD patients meeting DSM-IV criteria for MDD with moderate or severe episodes were recruited, together with 15 healthy controls. We used T2-weighted 2D Fast Spin Echo (FSE) and T1-weighted 3D MPRAGE sequences at 4.7 T to compare hippocampal subfield volumes at 0.09 µl voxel volume. Participants were administered the Wechsler Memory Scale. RESULTS: MDD patients underperformed in several episodic visual memory tasks, as well as in visual working memory, compared to healthy controls. Global hippocampal volumes were similar between groups; however, MDD patients showed significantly reduced DG volumes within the hippocampal body. Duration of depression correlated with MDD patients׳ total volumes in the hippocampal body and CA1-3 and DG subfields within it. LIMITATIONS: Our study sample was relatively small and the majority of patients were on antidepressant treatment. CONCLUSIONS: Our findings suggest that DG volumes in particular may be worthy of further study to further elucidate their precise role in MDD, both by itself as well as in relation to memory.

Structural changes in hippocampal subfields in major depressive disorder: a high-field magnetic resonance imaging study.

BACKGROUND: Magnetic resonance imaging (MRI) has shown lower hippocampal volume in major depressive disorder (MDD). Preclinical and postmortem studies show that chronic stress and MDD may affect hippocampal subfields differently, but MRI spatial resolution has previously been insufficient to measure subfield volumes. METHODS: Twenty MDD participants (9 unmedicated and 11 medicated, both > 6 months) and 27 healthy control subjects were studied. We used T2-weighted two-dimensional fast spin echo and T1-weighted three-dimensional magnetization prepared rapid acquisition gradient-echo sequences at 4.7 T to compare hippocampal subfield volumes at .09 µL voxel volume. RESULTS: Unmedicated MDD participants had a lower dentate gyrus volume than control subjects or medicated MDD participants and a lower cornu ammonis (CA1-3) volume in the hippocampal body subregion than control subjects. CONCLUSIONS: Hippocampal volumes in unmedicated MDD showed evidence of localization to specific subfields and subregions, findings that appear, on the surface, consistent with preclinical evidence for localized mechanisms of hippocampal neuroplasticity. Strengths include in vivo measurement of entire hippocampal subfields and separation between unmedicated and medicated MDD. Limitations include power to control for multiple comparisons and that MRI landmarks approximate the subfields defined by cellular microstructure.

Fronto-limbic volumetric changes in major depressive disorder.

BACKGROUND: Fronto-limbic dysregulation in major depressive disorder (MDD) may be influenced by early life stress and antidepressant treatment. The present structural MRI study aimed to determine the relationship between amygdala, cingulate and subgenual prefrontal cortex volumes in MDD and their associations with child abuse and antidepressants. METHODS: Right-handed subjects (21-50 years), meeting DSM-IV criteria for MDD, either with (n=19) or without (n=20) childhood sexual or physical abuse. Healthy controls (n=34) were matched for age, sex, education and smoking. 3D-MPRAGE images with a spatial resolution of 1.5 mm×1.0 mm×1.0 mm were acquired with a Siemens Sonata 1.5 T system. Volumes of subgenual prefrontal cortex, amygdala and affective, cognitive, superior and posterior divisions of cingulate cortex were analyzed using DISPLAY software using reliable volumetric protocols. Groups were compared using ANCOVA, with intracranial volume as a covariate. RESULTS: MDD subjects had low cingulate (cognitive division) and high amygdala volumes. Low cingulate volume was related to abuse and treatment history. Amygdala volume was predicted by subgenual prefrontal and cingulate (cognitive division) volumes and the presence of paracingulate cortex. LIMITATIONS: This study was cross sectional and the sample size was limited for subgroup and correlational analyses. SUMMARY: Our data suggest that MDD may be associated with alterations in anterior cingulate cortex and amygdala. Morphological variation, early stress and stress-protective factors may contribute to differences in fronto-limbic structures in MDD.

Structural organization of the prefrontal white matter pathways in the adult and aging brain measured by diffusion tensor imaging.

Previous diffusion tensor imaging (DTI) studies confirmed the vulnerability of frontal callosal fibers to normal aging. The present study extended this examination systematically to other prefrontal white matter regions. Structural magnetic resonance imaging and DTI datasets were acquired from 69 healthy subjects aged 22-84 years. The prefrontal white matter was parcellated into several anatomical sub-regions: medial and lateral orbitofrontal white matter, dorsolateral prefrontal white matter, and medial prefrontal white matter, using reliable DTI-tractography protocols. Tract-specific characteristics were calculated using Matlab. Regression models were used to determine the relationship between age and structural integrity of white matter tracts. The results of our study demonstrate regional age-related changes in the prefrontal white matter tracts of the human brain. This study was cross-sectional and therefore additional longitudinal studies are needed to confirm our findings.

Structural changes in the hippocampus in major depressive disorder: contributions of disease and treatment.

BACKGROUND: Previous magnetic resonance imaging (MRI) studies of patients with major depressive disorder (MDD) have consistently shown bilateral and unilateral reductions in hippocampal volume relative to healthy controls. Recent structural MRI studies have addressed the question of whether changes in the volume of hippocampal subregions may be associated with MDD. METHODS: We used a comprehensive and reliable 3-dimensional tracing protocol that enables delineation of hippocampal subregions (head, body, tail) to study changes in the hippocampus of patients with MDD. We recruited 39 MDD patients (16 medicated, 23 unmedicated) and 34 healthy age- and sex-matched controls. We acquired images using a magnetization-prepared rapid acquisition gradient echo sequence on a 1.5-T scanner with a spatial resolution of 1.5 mm x 0.5 mm x 0.5 mm. We performed volumetric analyses, blinded to diagnosis, using the interactive software package Display. All volumes were adjusted for intracranial volume. RESULTS: We found a significant reduction in the volume of the hippocampal tail bilaterally, right hippocampal head and right total hippocampus in MDD patients. Medicated MDD patients showed increased hippocampal body volume compared with both healthy controls and unmedicated patients. LIMITATIONS: This study was cross-sectional. Further prospective studies are needed to determine the direct effect of antidepressant treatment. CONCLUSION: Our results suggest that decreased hippocampal tail and hippocampal head volumes could be trait changes, whereas hippocampal body changes may be dependent on treatment. We showed that long-term antidepressant treatment may affect hippocampal volume in patients with MDD.

Selective effects of aging on brain white matter microstructure: a diffusion tensor imaging tractography study.

We examined age-related changes in the cerebral white matter. Structural magnetic resonance images (MRIs) and diffusion tensor images (DTIs) were acquired from 69 healthy subjects aged 22-84 years. Quantitative DTI tractography was performed for nine different white matter tracts to determine tract volume, fractional anisotropy (FA), mean diffusivity (MD), axial, and radial diffusivities. We used automated and manual segmentation to determine volumes of gray matter (GM), white mater (WM), cerebrospinal fluid (CSF), and intracranial space. The results showed significant effects of aging on WM, GM, CSF volumes, and selective effects of aging on structural integrity of different white matter tracts. WM of the prefrontal region was the most vulnerable to aging, while temporal lobe connections, cingulum, and parieto-occipital commissural connections showed relative preservation with age. This study was cross-sectional, and therefore, additional longitudinal studies are needed to confirm our findings.